NO115246B - - Google Patents

Description

Process for the manufacture of steroids.

This invention relates to the synthesis of

valuable steroids. According to the invention, a forward-I

procedure for preparing a compound of the formula

where the 4,5-position has a double bond or is saturated, where R denotes -H, R' denotes -OH, or R and R' together denote = O or a group that can be converted thereto by hydrolysis, R" denotes H and R' " denotes (|3)-OH or R" and R'" together means = 0, Y denotes -H, -OH or -O-(acyl), and Z denotes either -H or (a)-OH characterized in that a compound having the formula wherein the 4,5-position has a double bond or is saturated and R' R', Y and Z are as defined above is reacted with hydrogen fluoride and, if desired, the resulting 9a-fluoro-lip-hydroxy-steroid is oxidized to its 11-keto derivative. The 9p, 11p-oxido-steroids of the pregnane series which can be used in the present method are prepared from the corresponding 9a-bromo, 11p-hydroxy derivatives by splitting off hydrogen bromide from the latter. Among the 9 a-bromo, 11 p-hydroxy esteriods of the pregnane series which can be used for the production of the starting material in the process according to the invention are: 9 a-bromo-A<4->pregnen-li p,. 17 a, 21-triol-3, 20-dione (also called 9 rx-bromo-17 a-hydroxy-corticosterone; 9 a-bromohydro-cortisone or 9 a-bromo compound-F), 9 a-bromo-corticosterone, and esters thereof [especially carboxylic esters, such as lower alkanoic acid esters, (e.g. acetate)], and which 9 α-bromo-21-oxysteroids are prepared, e.g. by the method described in J. Am. Chem. Soc, 75, 2273 (1953); 9α-bromo, 11β-hydroxyprogesterone, and 9α-bromo-11β-17α-dihydroxyprogesterone, which 9α-bromo-21-substituted steroids are prepared by the method described below. The resulting 9β, 11β-oxido-steroids, namely 9β, 11β-oxido-A4-pregnene-17α-21-diol-3, 20-dione (also called 9β, 11β-oxido-17α , 21-dihydroxy-progesterone), 9p, 11p-oxido-A4-pregnen-21-ol-3,20-dione (also called 9p, 11p-oxido-21-hydroxyprogesterone), esters thereof, 9p, 11β-oxido-<p>rogesterone, and 9β, 11β-oxido-17α-hydroxyprogesterone are then treated with a hydrofluorinating agent, e.g. hydrofluoric acid, in an alcohol-free solvent, preferably at approx. 0° C, so the corresponding 9α-fluoro, 11β-hydroxy derivatives are formed, namely: 9α-fluorohydrocortisone, 9α-fluorocorticosterone, esters thereof, 9α-fluoro-11β-hydroxyprogesterone and 9α-fluoro -11 p, 17 a-dihydrooxy-progesterone. These 9 α-fluoro, 11 β-hydroxy steroids can then be oxidized to the corresponding keto compounds (if desired) by means of common oxidation methods, e.g. chromic acid in glacial acetic acid.

The steroids of the pregnane series which have a 9 α-fluoro substituent and an 11-keto or 11 β-hydroxy substituent (and the esters of the

which has a 21-hydroxy group) has — contrary to what one would expect — corticoid activity in liver glycogen tests.

This activity is far greater than the activity of corresponding steroids in which another halogen radical is substituted for the 9 α-fluorine group, e.g. those discussed in J. A. C. S. Vol. 75, 2273 (1953), and are also greater than the activity of the corresponding steroids not substituted in the 9-position. (The compounds according to the invention which have a 21-hydroxy group can be directly obtained as or easily converted into the corresponding fatty acid esters, especially lower alkanoic acid esters).

For a better understanding of the above general and the subsequent detailed description of the invention, reference should be made to the following schematic overview:

The following examples explain the invention in more detail (all temperatures are given in degrees Celsius and all dilutions are with water unless otherwise stated):

Example A.

Preparation of A4- pregnene- 9 $, 11 (3-oxido- 17 a, 2l- diol- 3, 20-dione ( IX)

or its 21-acetate (V)

(a) A4- pregnene- 9 p, 11 $- oxido- 17 a, 21-diol- 3, 20- dione ( IX) from 9 a- bromo-A4- pre<g>'-nen- llfi, 17 a , 21- triol- 3, 20- dione 21- acetate ( I)

A solution of 103 mg of potassium bicarbonate in 1 ml of water. The resulting solution is allowed to stand at room temperature for 18 hours, after which 4 ml of water is added and the solution is freed of methanol in vacuo. To the residue is added chloroform and after mixing and separation of the layers, the chloroform solution is washed with water and dried over sodium sulfate. Evaporation of the solvent gives a residue (approx. 82 mg) which easily crystallizes from acetone. The pure A<4->pregnene-9 (3, 11 p-oxido-17 a, 21-diol -3,20-dione has the following properties: m.p., approx. 206-208° C

[a] 22 + 23° (c = 0.75 in CHCl:i), Val) s"

D max. 243 mji (s = 13,700); analysis [calculated for CaiHasbr, : C = 70.02; H = 7.77; found (approx.) C = 70.39; H = 7.95].

( a: alternative) A4- pregnene- 9 p, 11$-17a, 21- diol- 3, 20- dione- 21- acetate ( V) from 9 a- bromo- A4- pregnene- ll p, 17 a-triol - 3, 20-dione-21-acetate (I).

A solution of 2.5 g of 9α-bromo-A4-pregnene-lip, 17α, 21-triol-3,20-dione-21-acetate and 6.25 g of potassium acetate in 190 g of absolute alcohol is boiled with reflux for 50 min. After adding 20 ml of water, the solution is concentrated in vacuo until crystallization begins. Water (50 ml) is added again and the crystallization is finished in a refrigerator. The fraction obtained first (approx. 1.31 g) melts at approx. 209.5—210.5° C and a next fraction (approx. 291 mg) which melts at approx. 206-208° C is obtained by concentrating the mother liquors. The analytically pure material obtained by crystallization from acetone melts at approx. 210—212° C and has [a] ^<3->|-

41° (c = 0.70 in CHCl 2 ); l <alk-> 243 mu (e =

max.

15,500). Its approximate analysis [calculated for CasHaoOn : C = 68.30 ; H = 7.51) was C 69.02 ; H=7.42].

Example B.

Preparation of A4-pregnene-9p,11$-oxido-21-ol-3,20-dione-21-acetate (VI) from 9a-bromocorticosterone-acetate (II).

A solution of 253.8 mg of 9α-bromocorticosterone acetate and 625 mg of anhydrous potassium acetate in 18 ml of absolute alcohol is boiled under reflux for 50 min. After adding 10 ml of water, the alcohol is evaporated in vacuo and the remaining aqueous suspension is extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The remainder (approx. 205 mg) does not crystallize and is used in the next work step without further purification.

Example C.

Preparation of 9 p, 11 fi-oxidoprogesterone

(VIII)

(a) 9 a- bromo- 11 $- hydroxyprogesterone ( III) of A<4>'<9> <u~ >- pregnadiene- 3, 20-dione.

508 mg of A4'" <l1>-pregnadiene-3,20-dione (Shoppee and Reichstein (Heiv. 24,351 (1941)) suspended in dioxane and water is reacted with 309 mg of N-bromoacetamide and 3 ml of 1N aqueous perchloric acid, and the mixture is stirred carefully from time to time, until it has become completely clear. After a total reaction time of 1 hour, dilute sodium sulfite solution is added until the yellow solution has become almost completely decolorized. Then chloroform is added, and the small aqueous phase that floats above is separated from. The chloroform-dioxane phase, which contains the bromohydrin (III) is washed with dilute sodium bicarbonate and with water and dried over sodium sulfate. After removing the solvents in vacuo, a residue remains, which is dissolved in acetone. Crystallization takes place soon afterwards and the crystals obtained are recrystallized from acetone-hexane, whereby pure 9α-bromo-11β-hydroxy-progesterin is obtained, which has the following properties: m.p. approx. 148— 150° C (dec.) [a]D

alk.

+ i87° (c=1.0 in chloroform); X max. 243

m^i (e=16,100) ; X nujol 3.01 ^, 5.90 [ i, 6.00

max.

6.07 6.17 (x. Analysis (calculated for C2iH2903Br (409.4) ; C = 61.61 ; H = 7.14 ; found (approx.) ; C = 61.91 ; H = 6.92) .

(b) Preparation of 9p, 11$- oxydoprogesterone (VII) from 9a- bromo- 11$- hydroxyprogesterone (III).

103 mg of 9 a-bromo-11 p-hydroxyprogesterone is treated with 250 mg of potassium acetate as described in section a: alternative of ex. A. The resulting amorphous product,

representing 9 p, 11 p-oxidoprogesterone (ca. 90.6 mg) cannot be crystallized, even after chromatography, and is therefore used in the next working step without further purification.

Example D.

A4- pregnene- 9 p, 11 fi- oxydo- 17 a-ol- 3, 20-dione (VIII).

(a) 11 n- tosyloxy- 17 a- hydroxyprogesterone of lia, 17 a- dihydroxyprogesterone.

1.2 g of 11 a, 17 a-dihydroxyprogesterone is dissolved in 12 ml of anhydrous pyridine and to the resulting solution, which is placed in an ice bath, a solution of 1.4 g of p-toluenesulfonyl- chloride in alcohol-free chloroform. This addition requires approx. 2 hours, and after this the reaction mixture is allowed to stand for 4 hours at 0° C and optionally at room temperature overnight. Ice is added, and after <y>2 hours of stirring, the solution is evaporated in vacuum to a small volume. The residue is taken up in chloroform and water, and the chloroform solution is washed with cold dilute hydrochloric acid, dilute sodium bicarbonate and finally with water. The chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo. You get approx. 1.7 g of tosylate, which after recrystallization from acetone has the following properties: m.p. about. 143—146° C (dec.) ;

[a] q + 48° (c = 0.29 in chloroform) ;

ethanol 229 m^i (£ = 26,500) 274 rn^i (e =

max.

606), 285 mu (e = 305). I nujol 3.03 \ in (OH);

max.

5.88 |x, 5.99 \ i 6.05 (.i analysis: [calculated for C2sH™Or,S (500.63) : C = 67.17; H = 7.25;

S = 6.44; found (approx): C = 67.08; H = 7.52; S = 6.35]...

(b) A<4>'<n> W- pregnadiene- 17 a- ol- 3, 20- dione of 11 a- tosyloxy- 17 a- hydroxyprogesterone

1.19 g of 11α-tosuloxy-17α-hydroxyprogesterone is treated with 2.4 g of anhydrous sodium acetate in 25 ml. glacial acetic acid. The mixture is heated for 1 hour with reflux cooling. After evaporation of most of the acetic acid in vacuo, the residue is taken up in chloroform and extracted with water and then with dilute sodium bicarbonate and then again with water. The chloroform solution, which contains the desired product, is dried over sodium sulfate and the chloroform is removed in vacuo. The rest (approx. 693 mg) cry-

easily stalls from acetone and gives approx. 520 mg pure A4'0 <<11>>-pregnadiene-17 a-ol-3,20-dione which has the following properties: m.p. about. 214

—216° C [a]<23> + 67° (c = 0.82 in chloro-

form) ; 1 alk-239 rna (e = 18,450); X nuio1

max.. max. 2.88 L (OH), 5.87 M, (20-ketone), 5.99 L, 6.04 L, 6.16 L (A<4->3-ketone); analysis [calculated for CiMHjsOa (328.44): C = 76.79, H == 8.59;' found (approx.) C = 76.52; H = 8.46.]

(c) 9a-bromo-11p,17a-dihydroxyprogesterone (IV) of A4-1'^^-pregnadiene-

17 a-ol-3, 20-dione.

330 mg of A4'" ("»-pregnadien-17α-ol-3,20-dione is treated with 200 mg of N-bromoacetamide, and the reaction mixture prepared as described in section a of Example C. The resulting crude product (about 450 mg) is recrystallized from acetone-chlorine form and gives approx. 362 mg (85 percent) of pure 9α-bromo-11 (3, 17α-dihydroxyprogesterone, which has the following properties: m.p. approx. 189-191° C

(split.); [a]^<3> + 128° (c = 0.33 in chloro-

shape); A-<alk-> 243 mu (e = 16,700); l nui°<l>

max. max. 2.88 l (OH), 5.86 l (20-ketone), 6.04 l, 6.08 l (A<4->3-ketone); analysis [calculated for CiiiH 2 »O 4 Br (425.36) : C = 59.29; H = 6.87; Br = 18.79; found (approx.) C = 59.59; H = 6.81; Br = 18.61].

(d) Preparation of AA-pregnene-9$,11$-oxydo-17a-ol-3,20-dione (VIII) from 9a-bromo-11p,17a-dihydroxy-progesterone (IV).

A solution of 247 mg of 9α-bromo-11β, 17α-dihydroxyprogesterone and 630 mg of anhydrous potassium acetate is boiled with reflux for 90 min. The reaction mixture is worked up as described in section a of ex. A. The resulting crude residue gives pure A<4->pregnene-9 p, 11 p-oxido-17 a-ol-3,20-dione by recrystallization from acetone-hexane which has the following properties: m.p. about.

197-199° C [a] ^<3> + 6° (c = 0.32 in CHCl.,);

Å <alk-> 243 mii (8 = 15,200), 283 mu (e =

max.

630); l : nuJo1 2.86 u, 3.05 li, (OH), 5.89 u (20

max.

—CC), 6.04 l (A<4->3-ketone); analysis: [calcd for C21H28O4 (344.44): C = 73.22; H = 8.18; found (approx): C = 72.99; H = 8.11].

Example 1.

Preparation of 9α-fluorocortisone acetate (XVI)

(a) 9\ a- fluorohydrocortisone- acetate ( X) of A4- pregnen- 9 p, yl $- oxydo- 17 a, 21- diol-3, 20- dione- 21- acetate ( V)

Anhydrous hydrogen fluoride is added to a solution of 15 g of A4-pregnene-9p,11p-oxido-17a-21-diol-3,20-dione-21-acetate in 300 ml of chloroform (in a polyethylene container equipped with a inlet pipe made of copper). During the addition, the solution is kept in an ice bath and stirred by magnetic stirring, until the solution acquires a strong red colour. The inlet pipe is then replaced with a cap (made of polyethylene) and the reaction is allowed to proceed with stirring for 4-2 hours at 0° C. Concentrated sodium bicarbonate solution is then added until the mixture is slightly alkaline, and the two layers are separated. The now pale yellow chloroform solution is washed with 1 liter of water, and after drying over sodium sulphate it is evaporated to dryness in vacuo. The rest (approx.

17.0 g) is taken up in 125 ml of hot ethyl acetate,

the resulting suspension is filtered and the precipitate (on the filter) and the filtrate are treated as described below.

On cooling the ethyl acetate filtrate, a crystalline precipitate consisting of long needles mixed with small, heavy prisms falls out. This material (approx. 6.2 g) melts at approx. 228-230° C and consists mainly of pure 9α-fluorohydrocortisone acetate. It is recrystallized, for analysis, from ethyl acetate, and then melts at approx. 233— 234° C [Infrequently, products are available that soften at approx. 205—208° C, solidifies again, possibly melts at approx. 226—228° C true-probably due to pblymorphism]. It has the following properties: [a] ^<3> + 123° (c

= 0.64 in CHCb); l <alk-> 238 mLi (e =

max.

16,800); X nui°l 2.86 u, 3.01 u, 5.62 u, 5.78 u,

max.

5.83 l, 6.05 l; analysis (calculated for C->sH:nO(iF (422): C.= 65.39; H=7.39; F = 4.52; found (approx.): C = 65.32; H = 7 .26; F = 4.50].

By fractionating the ethyl acetate mother liquor, a new amount of 9α-fluorohydrocortisone acetate is obtained, whereby the yield rises to a total of 50 percent. 9α-fluorohydrocortisone acetate is approximately 11 times as active as cortisone acetate in rat liver. glycogen test and approx. 1-2 times as active as desoxycorticosterone-acetate in inducing sodium retention in rats. r The ethylene acetate-insoluble substance obtained on the filter (approx. 1.35 g) is recrystallized from acetone. The pure compound had the following properties: m.p. about. 259—262° C during decomposition, [a] ^<3>+ 262° (c = 0.53 in 95 per cent ethanol); a <alk-> 239 mn (E = 18,000); max. . nujo<l> 2;94 „ 3;03 ,,,, 5.75 „ 5.82 u, 6.07 max. 6.11 |i; analysis [calculated for C 2 H 2 O 402 ): C = 68.63; H = 7.51; found (approx.); C = 68.45; H = 7.17]. 1 ( b) 9 a- fluorohydrocortisone ( XI) of 9 a- fluorohydrocortisone acetate ( X). A solution of 11.4 mg of sodium in 1.9 ml of anhydrous methanol is added under nitrogen to a solution of 103.8 mg of 9α-fluoro-hydrocortisone acetate in 10 ml of absolute methanol. The mixture is allowed to stand at room temperature for 30 min. and acidified by adding a few drops of glacial acetic acid. Water is then added, and after the methanol has been removed in vacuo, the 9α-fluorohydrocortisone is extracted with ethyl acetate. The extract is washed with sodium bicarbonate solution and with water, and dried over sodium sulfate. When the solvent evaporates, a crystalline residue (approx. 92 mg) remains, which after recrystallization from 95% alcohol has the following properties: m.p. approx. 260-262° C (dec.): [a] ^ <3> -)- alk

139° (c = 0.55 in 95 per cent alcohol); A mo' 239

111 3.X •

miles (£ = 17,600); l n<ui>°<l> 3.01 u, 5.84 li, 6.07

max.

li, 6.20 li; analysis [calculated for CjiHaiO.-,F (380.4):' C = 66.30; H=7.68; found (approx): C = 66.49; H = 8.22]. 9 The α-fluorohydrocortisone has approximately the same biological activity as its acetate.

(c) 9a-fluorocortisone-acetate (XVI) of

9 a- fluorohydrocortisone acetate ( X).

A solution of 10 mg of chromic acid in 2 ml of acetic acid is added to a solution of 31.2 mg of 9"-fluorohydrocortisone acetate in 3 ml of glacial acetic acid. Half an hour later, 1 ml of methanol is added, and the resulting mixture is concentrated in vacuo. The residue is distributed between chloroform and water, and the resulting ■ chloroform extract is washed with water, sodium bicarbonate solution and then water again. After drying over sodium sulfate and evaporation of the solvent in vacuo, the residue (approx. 25 mg) is crystallized from 95% alcohol. The pure )α-fluorocortisone acetate has the following properties: m.p. about. 254—255° C [a] ^<3> + 155°

(c = 0.45 in (CHCls); Å <alk-> 234 nui (e =

max.

L7,000); A nuJQl 2.86 li, 5.72 u, 5.78 11, 5.83 u,

max. r 3.05 li; analysis [calculated for CmHooOhF: C = 65.70; H = 6.95; found (approx): C = 65.62;

H = 7.19]. 9 α-Fluorocortisone acetate is about 10 times as active as cortisone acetate in the root-teleliver glycogen test. (d) 9α-fluorocortisone (XVII) from 9α-fluorocortisone acetate (XVI). 25 mg of 9α-fluorocortisone acetate is de-acetylated as described in section b of example 1. Approx. 18.4 mg of product is obtained, which upon crystallization from 95 percent alcohol gives approx. 14 mg of 9α-fluorocortisone, which has the following properties: m.p. about. 261—262° C [a] ^<3>

144° (c = 0.41 in CHCl0; A alk- 234 mu (E =

max.

16,000); A nui°<l> 2.88 li, 5.87 li, 6.08 u; analysis

max.

[calculated for GmHutOoF; C = 66.65; H = 7.19; found C = 66.50; H=6.98].

Example 2.

9 a- fluorocorticosterone- acetate ( XII) of A<4->pregnen- 9 |3, 11 fi- oxydo- 21- ol- 3, 20- dione-21-acetate (VI).

Anhydrous hydrogen fluoride is added to an ice-cooled solution of 100 mg of A<4>, pregnene-9 (3, 11 (3-oxido-21-ol-3,20-dione-21-acetate in 10 ml. chloroform. After 1 hour at 0° C, more chloroform is added, and the solution is extracted with sodium bicarbonate solution and finally dried over sodium sulfate. The residue (approx. 125 mg) is taken up in hot ethyl acetate and purified as described in section a of example 1. The pure 9 a-Fluoro-corticosterone acetate has the following properties: mp about 212-214° C, [a] ^3-|-184° (c = 0.11 in CHCls); the activity is four times that of cortisone acetate in the liver glycogen test and over 10 times that of deoxycorticosterone acetate in the sodium retention test.

By using the method according to section b in example 1, 9α-fluorocorticosterone acetate can be hydrolysed to 9α-fluorocorticosterone (XIII). Following the method in section c in example 1, 9α-fluorocorticosterone acetate can be oxidized to 9α-fluoro-11-dehydrocorticosterone acetate (XVIII). Following the method in section b in example 1, 9α-fluoro-11-dehydrocorticosterone acetate can be hydrolysed to 9α-fluoro-11-dehydrocorticosterone (XIX).

Example 3.

9 a- fluoro- 11 $- hydroxyprogesterone ( XIV) of 9$, 11 fi- oxydo- progesterone ( VIII).

63.2 mg of 9 p, 11 p-oxydoprogesterone in 6.3 ml of chloroform is reacted for 1 hour with gaseous hydrogen fluoride at 0° C. The reaction mixture is worked up as described in section a of example 1 and the residue obtained (approx. 61 mg ) is crystallized from acetone-hexane. Pure 9 α-fluoro-11 β-hydroxyprogesterone is obtained after recrystallization from absolute alcohol and has the following properties: m.p. about. 216-217°C; [a]D + 191° 23

(c = 0.74 in chloroform); activity equal to that of cortisone acetate in the liver glycogen test, and twice that of desoxycorticosterone acetate in the sodium retention test.

By oxidation of 9 a-fluoro-11 p-hydroxy-progesterone with chromic acid on the i

section c of ex. In the indicated manner, 9 α-fluoro-ll-ketoprogesterone (XX) is obtained.

Example 4. 9a-fluoro-11p,17a-dihydroxyprogesterone (XV) of A-'-pregnene-9p,11fi-oxydo-17a-ol-3,20-dione (VIII) 42 mg A< 4->pregnene-9p,11p-oxydo-17a-ol-3,20-dione is dissolved in 3 ml of chloroform and reacted with gaseous hydrogen fluoride at 0° C. for 1 hour. The reaction mixture is worked up as described in section a of example 1 and the resulting residue (approx. 30 mg) gives, after crystallization from acetone-chloroform-hexane, pure 9α-fluoro-11β, 17α-di<y->droxyprogesterone, which has the following self-23 creates: m.p. 274-275°C; [a] D + 136° (c = 0.3 in dioxane); activity y3 of cortisone acetate in the liver glycogen sample. 9α-fluoro-11β, 17α-dihydroxyprogesterone can be oxidized to 9α-fluoro-11-keto-17α-hydroxyprogesterone (XXI) by the method described in section c of example 1.

Claims (3)

1. Process for the preparation of a compound with glucocorticoid activity and with the formula where the 4,5-position has a double bond or is saturated, where R denotes -H, R' denotes -OH, or R and R' together denote = O or a group that can be converted thereto by hydrolysis, R" denotes H and R'" be denotes (P)-OH or R" and R'" together means = o, Y denotes -H, -OH or -O-(acyl), and Z denotes either -H or (a)-OH, characterized in that a 9 P , 11 p -oxido-steroid having the formula where the 4,5-position has a double bond or is saturated and R, R', Y and Z are as defined above is reacted with hydrogen fluoride and, if desired, the resulting 9 a -fluoro-11 (5-hydroxy-steroid is oxidized to its 11-keto derivative. 2. Method according to claim 1, characterized in that the hydrogen fluoride is reacted with the 9 |3, 11 (3-oxido-steroid in an alcohol-free solvent. 3. Method according to claim 1 or 2, characterized in that the 9 p, 11 p-oxido-steroid is A<4->pregnene-9 p, 11 p-oxido-17 a, 21-diol-3,20-dione or A<4->pregnen-9p,-11p-oxydo-21-ol-3,20-dione or an ester thereof, or is 9p, 11p-oxidoprogesterone or A<4->pregnen-9p , 11 α-oxydo-17 α -ol-3,20-dione.